Crystal structure of UDP-glucose pyrophosphorylase from Yersinia pestis, a potential therapeutic target against plague

Abstract

Yersinia pestis, the causative agent of bubonic plague, is one of the most lethal pathogens in recorded human history. Today, the concern is the possible misuse of Y. pestis as an agent in bioweapons and bioterrorism. Current therapies for the treatment of plague include the use of a small number of antibiotics, but clinical cases of antibiotic resistance have been reported in some areas of the world. Therefore, the discovery of new drugs is required to combat potential Y. pestis infection. Here, the crystal structure of the Y. pestis UDP-glucose pyrophosphorylase (UGP), a metabolic enzyme implicated in the survival of Y. pestis in mouse macrophages, is described at 2.17 Å resolution. The structure provides a foundation that may enable the rational design of inhibitors and open new avenues for the development of antiplague therapeutics.

Keywords: UDP-glucose pyrophosphorylase; Yersinia pestis; drug targets; galU; plague.

Figure 1

(a) Stereoview of a cartoon representation of the crystal structure of Y. pestis UGP solved at 2.17 Å resolution (PDB entry 6mnu) illustrating the tetrameric unit with individual chains colored as follows: chain A, green; chain B, cyan; chain C, magenta; chain D, yellow. (b) Stereoview of a cartoon representation of chain A with secondary-structure elements colored as follows: α-helices, cyan; loops, magenta; β-strands, red.

Figure 2

Stereoview of a representative fit of residues Tyr215–Leu224 to the final 2F _o − F _c electron-density map (blue; 2.17 Å resolution, contoured at a 1.0 r.m.s.d. level, PDB entry 6mnu).

Figure 3

(a) Stereoview of superimposed monomers of Y. pestis UGP (blue; PDB entry 6mnu, chain A, 2.17 Å resolution), E. coli UGP (cyan; PDB entry 2e3d, chain A, 1.95 Å resolution), E. amylovora UGP (orange; PDB entry 4d48, chain A, 2.46 Å resolution) and B. ambifaria (tan; PDB entry 5ve7, chain A, 2.3 Å resolution). (b) Stereoview of superimposed monomers of Y. pestis UGP (blue; PDB entry 6mnu, chain A) and H. pylori UGP (magenta; PDB entry 3juk, chain A, 2.3 Å resolution).

Figure 4

(a) Stereoview of chain A of Y. pestis UGP illustrating the modeled position of UDP-glucose (blue spheres) based on superimposition of the coordinates onto the structure of chain A of H. pylori UGP complexed with UDP-glucose (PDB entry 3juk). (b) Stereoview of a structural comparison of the active-site residues of Y. pestis UGP (C atoms in gray, O atoms in red, N atoms in blue) superimposed onto the active-site residues of H. pylori (chain A, C atoms in cyan) bound to UGP-glucose (C atoms in purple, phosphate atoms in orange). (c) Stereoview of a structural comparison of Y. pestis UGP active-site residues superimposed onto the active-site residues of B. ambifaria UGP (C atoms in cyan) bound to UTP (C atoms in purple, phosphate atoms in orange) (PDB entry 5ve7, chain A).